This K23 application proposes to support the research training goals of candidate Lynne R. Sheffler, MD. A 5-year research training plan is outlined which includes educational coursework, focused scientific mentoring and clinical research. The candidate's primary long-term scientific goal is to become an independent clinician researcher with expertise in 1) the motor relearning and neuroplastic effects of neuromuscular electrical stimulation (NMES) for persons with central nervous system (CNS) paralysis and 2) the application of functional magnetic resonance imaging (fMRI) techniques to quantitate neuroplastic responses to NMES and other rehabilitation interventions. The candidate's short-term scientific goals, which form the basis of the K23 career development plan, are 1) to develop expertise in NMES-mediated motor relearning;2) to gain proficiency with fMRI as an assay for NMES-mediated neuroplasticity;and 3) to acquire additional research skills for successful transition to independence. The research focus is on footdrop, a common post-stroke impairment of ankle dorsiflexion characterized by dragging of the foot during walking, which results in an inefficient and unsafe gait pattern. A series of three research protocols is proposed, over a 5 year period, to develop and implement an ankle dorsiflexion fMRI paradigm in stroke survivors which will allow the comparison of the therapeutic effect of Contralaterally-controlled NMES (CCNMES) versus cyclic peroneal NMES to enhance motor recovery of the ankle when applied in the acute post-stroke period. Protocol 1 will develop the ankle dorsiflexion fMRI paradigm. Protocol 2 will apply the fMRI paradigm to acute post-stroke patients to document changes in cortical and subcortical activation patterns associated with natural recovery. Protocol 3 is a pilot randomized trial which will compare the effect of CCNMES to cyclic peroneal NMES on motor impairment and fMRI activation patterns. The neuroplasticity literature suggests that the ability of NMES to affect cortical reorganization and motor recovery may be greatest in the acute post-stroke period (defined as <3 months post-stroke). The application of an fMRI ankle dorsiflexion fMRI paradigm to identify and characterize a central mechanism for NMES-mediated lower extremity motor relearning in the acute post-stroke period will have broad implications in the clinical care of stroke patients. The K23 career development plan identifies three NIH-funded clinical researchers, John Chae, MD, Stephen M. Rao, PhD, and Jayme S. Knutson, PhD, to oversee the candidate's career development and training activities during the K23 award period. The candidate is further supported by a research infrastructure that includes the Cleveland FES Center, Case Western Reserve University, MetroHealth Medical Center and the Schey Center for Cognitive Neuroimaging (Cleveland Clinic). This K23 application will explore critical questions regarding post-stroke motor relearning and NMES-mediated neuroplasticity and will provide a solid training foundation to transition the candidate to independent clinical researcher status. PUBLIC HEALTH RELEVANCE: There is a critical need to train physician researchers capable of bridging basic neuroscience and engineering research and clinical care so as to facilitate the translation of rehabilitation interventions that may enhance motor function and quality of life for patients with CNS paralysis. The K23 funding mechanism will provide the candidate with a unique set of skills as an expert in NMES-mediated motor relearning, post-stroke neuroplasticity and the application of functional MRI to elucidate cortical mechanisms of post-stroke motor recovery.